Z-di-lower alkyl-



United States Patent IMPROVEMENT EN THE PHNACUL-PKNACQLONE REARRANGEMENT0F LZ-DI-LOWER ALKYL- 1,2=BllS-PYRIDYLFTHANE-LZ-DIOLSr T0 PRO DUCE2,2-llll-LQWER ALKYL-1,2-EES@YRH)YL- ETHANE-l-UNES William LassiterYost, Long Valley, Ni, assignor to (Iiha Qtli'ptllfliiflil, a summationof Delaware No Drawing. Filed Nov. 1, 1961, Ser. No. 149,225

, Claims. (Cl. 260295) The present invention is a new and improvedmethod for the preparation of pinacolone rearrangement products.

2,2-di-l0wer alkyl-1,2 bis-pyridyl-ethan-l-ones and 1,2-

di-lower alkyl 2,2-bis-pyridyl-ethan-l-ones, particularly the compoundsof the formulae:

and

in which each of the groups R and R stands for 3-pyridy1 or 4-pyridylradical, and each of the groups R;, and R represents lower alkyl,particularly methyl, and which are known to inhibit certain functions ofthe adrenal cortex gland, are prepared by pinacolone rearrangement(treatment with a strong acid) of 1,2-di-loweralkyl-LZ-bispyridyl-ethan-1,2-diols, especially of diols of the formula:

in which R R R and R, have the previously-given meaning, or of saltsthereof. The pinacolone rearrangement is carried out by heating the diolcompound with a strong Lewis acid, particularly sulfuric acid, andseparatin the resulting mixture of ketone compounds into singlecompounds (US. Patent No. 2,966,493 of December 27, 1960). It has beenestablished that the 2,2-dilower allryl-l,2-bis-pyridyl-ethan-l-ones, inwhich pyridyl represents 3-pyridyl or 4-pyridyl, particularly the 2-methyl-l,2-bis-(3-pyridyl)-propan-l-one of the formula:

(llHs J-t-tQ N 0 CH3 N (generic name: methopyrapone) have certainpharmacological advantages over the 1,2-di-loweralkyl-2,2-bispyridyl-ethan-l-ones, particularly the 3,3-bis-(3-pyridyl)-butan -2-one of the formula:

(I311; f" N (I320 N which are simultaneously formed in the pinacolonerearrangement; separation of the resulting mixture and recovery of thedesired compounds are, therefore, necessary.

The separation of the reaction mixture into its two constituents may becarried out by fractional crystallization, fractional distillation undergreatly reduced pressure, adsorption on an adsorbent and subsequentfractional elution, conversion of the mixture into a mixture offunctional derivatives, such as the oximes, separation of the mixture ofderivatives into the single derivatives and liberating the desiredketone from its functional derivative, or any other 3,ll&d% PatentedJan. 21, N554 suitable separation procedure. Although separation of therearrangement mixture can be achieved, the methods are rather cumbersomeand a substantial loss of the de sired compound cannot be avoided.

A11 object of this invention is to provide an improved procedure for thepreparation of the 2,2-di-lower alkyll,2bis-pyridyl-ethan-l-0nessubstantially free from the simultaneously formed 1,2-di-loweralkyl-2,2-bis-pyridylethan- 1 -one.

Another object of this invention is to provide an improved procedure forthe preparation of 2,2-di-lower alkyll,Z-bis pyridyl-ethan-l-ones insubstantially pure form and satisfactoryyields.

Another object of this invention is to provide an improved procedure forthe preparation of 2,2-di-l0wer alkyl- 1,2-bis-pyridyl ethanl-ones insubstantially pure form and satisfactory yields, which does not requirea separation of a resulting mixture.

Other objects of this invention will become evident from the subsequentdescription of the invention.

I have now found that the process for the preparation of a 2,2-di-loweralky 1,Z-biS-pyridyI-ethan-l-one, particularly of a compound of theformula:

s R C( Rz 0' 1'1. in which R R R and R have the previously-givenmeaning, by treatment with a strong acid reagent of a 1,2- di-lowerall-ryl-1,2-bis-pyridyl-ethan-l,Z-diol, particularly of a compound ofthe formula:

in which R R R and R have the previously-given meaning, or of a saltthereof, at an elevated temperature, can be improved unexpectedlybyusing as the strong acid reagent concentrated sulfuric acid containingsulfur trioxide.

The product, i.e. the 2,2-di-lower alkyl-l,2-bis-pyridylethan-l-one,resulting from such improved procedure is substantially free from a1,2-Ji-lower alkyl-2,2-bis-pyridylethan-l one, particularly from acompound of the formula:

s R JRz i=0 it.

in which R R R and R have the previously-given meaning, and, if desired,may be converted into a ketonic derivative, a salt or a salt of aketonic derivative thereof.

A salt of the starting material is an acid addition salt, particularlyan addition salt with a mineral acid, such as hydrochloric, hydrobromic,sulfuric, phosphoric acid and the like.

The concentrated sulfuric acid used as the rearrangement reagentintheprocess of this invention, contains from about 0.1 percent to about20 percent by weight, preferably from about 0.5 percent to about 5percent by weight, of sulfur trioxide. Commercially availablepreparations, such as oleum, may be used; a reagent containing less than20 percent sulfur trioxide, maybe prepared, for example, by dilutingfuming sulfuric acid, containing, for example, 20 percent of sulfurtrioxide, with concentrated sulfuric acid (i.e. 96 percent sulfuricacid). A 1:1- mixture of 20 percent fuming sulfuric acid and 96 percentsulfuric acid represents a reagent containing 1.13 percent by Weightfree sulfur trioxide, whereas a 2:1-mixture of 20 percent fumingsulfuric acid and 96 percent sulfuric acid yields a reagent containing11.13 percent by weight sulfur trioxide.

The rearrangement takes place at an elevated temperature, particularlyat a temperature of from about 40 to about 150, preferably from about 60to about 100; the elevated temperature is maintained until no diolstarting material can be detected any longer. The reaction mixture isworked up as usual, i.e. the acidic reaction mixture, preferably afterdiluting it, is neutralized or basified, for example, by treatment witha base, e.g. sodium hydroxide, ammonium hydroxide, sodium carbonate andthe like, and the desired product is extracted from the neutral or basicaqueous mixture with a suitable organic solvent e.g. ethyl acetate,benzene, toluene, cyclohexane, methyl-cyclohexane and the like, or asolvent mixture; the desired material is then recovered bycrystallization and is further purified by the usually employed methods.

The preparation of 2-methyl-l,2-bis-(3-pyridyl)-propan-l-one,substantially free from 3,3-bis-(3-pyridyl)- butan-Z-one according tothe process of this invention, which comprises reacting2,3-bis-(3-pyridyl)-butan-2,3- diol with sulfuric acid containing fromabout 0.1 percent to about 20 percent by weight, preferably from about0.5 percent to about percent by Weight, of sulfur trioxide as the strongacid reagent at an elevated temperature, particularly at a temperatureof from about 60 to about 100", represents a preferred procedure. Theisolation of the desired 2-methyl-1,2-bis-(3-pyridyl)-propan-1-one maybe carried out according to known methods, for example, aspreviously-shown.

In the process of this invention such starting materials are preferablyused which lead to final products mentioned in the beginning aspreferred embodiments of the invention.

This is a continuation-in-part application of my application Serial No.96,111, filed March 16, 1961 now abandoned.

The following examples are intended to illustrate the invention and arenot to be construed as being limitations thereon. Temperatures are givenin degrees centigrade.

Example 1 A total of 24.4 g. of 2,3-bis-(3-pyridyl)-butan-2,3-di0l isadded to a mixture of 100 g. of fuming sulfuric acid (containing 20percent of sulfur trioxide) and 50 g. of 96 percent concentratedsulfuric acid while stirring. The resulting solution is maintained at 75for seven hours and is then allowed to cool to room temperatureovernight. The cold solution is poured slowly over crushed ice; theaqueous solution is made basic (pH about with a 50 percent solution ofsodium hydroxide in water. The oily organic material is extracted withethyl acetate, the organic extract is washed with a saturated aqueoussodium chloride solution, dried over sodium sulfate and evaporated todryness. The residue (9.6 g.) is dissolved in a mixture of 2.6 ml. ofdiethyl ether and 1.6 ml. of pentane; the solution is seeded and allowedto stand at 4 overnight. The solid material is filtered off and washedwith a lzl-inixture of diethyl ether and pentane to yield 8.39 g. of2-rnethyl-1,2-bis-(3-pyridyl)-propan-1-one, M.P. 45- 49, which is freefrom any substantial amount of 3,3-bis- (3-pyridyl)-butan-2-one.

In the above example, 2,3-bis-(3-pyridyl)-butan-2,3- diol may bereplaced by 3,4-bis-(3-pyridyl)-hexan-3,4-diol or2,3-bis-(4-pyridyl)-butan-2,3-dio1 as the starting materials; upontreatment with concentrated sulfuric acid containing sulfur trioxidethese starting materials yield theZ-ethyl-l,2-bis-(3-pyridyl)-butan-1-one and the Z-methyl-1,2-bis-(4-pyridyl)-propan-1-one (M.P. 7576) substantially free from the4,4-bis-(3-pyridyl)-l1exan-3-one and Example 2 A solution of 42480 g. of2,3-bis-(3-pyridyl)-butan- 2,3-diol in a mixture of 133000 g. of fumingsulfuric acid (containing 20 percent of sulfur trioxide) and 13000 g. ofconcentrated sulfuric acid (96 percent) is heated at -95 for 3%. hours.The reaction mixture is allowed to cool overnight and is then pouredonto ice. The aqueous acidic solution is made alkaline with a 27 percentaqueous solution of ammonium hydroxide; the oily product is extractedwith toluene, and the organic solution is decolorized by treatment withcharcoal, and evaporated. The crude product is dissolved in abenzenemethylcyclohexane mixture, treated with a small amount ofaluminum oxide and then chilled. The resulting crystalline 2-metl1yl-1,2-bis-(3-pyridyl)-propan-1-one is filtered off, washed withmethylcyclohexane and dried to yield 15600 g. of pure product, whichmelts at 50-51 and contains less than 0.25 percent of3,3-bis-(3-pyridyl)-butan-2-one.

Example 3 A total of 44600 g. of the crude product obtained from arearrangement procedure carried out according to Example 2, is dissolvedin 10 volumes of a toluene-methylcyclohexane solution at 40 50, andtreated for one hour with a charcoal preparation. The solid material isfiltered oil, the filtrate is slowly cooled to 27, seeded, then cooledwith water and later with brine. The crystalline 2-methyl-1,2-bis-(3-pyridyl)-propan-1-one is filtered off and dried at 25-30" toyield 35000 g. of the pure desired product. The residue from the motherliquors is again treated with sulfuric acid containing sulfur trioxideand another 3900 g. of pure 2-methyl-1,2-bis-(3-pyridyl)-propan-1-onecan be recovered; total yield: 38900 g.

What is claimed is:

1. In the process for the preparation of 2,2-di-loweralkyl-1,2-bis-pyridyl-ethan-l-ones by treatment with a strong acidreagent of a member selected from the group consisting of a 1,2-di-loweralkyl-1,l-bis-pyridyl-ethan-1,2- diol and a salt thereof, theimprovement which comprises using as the strong acid reagentconcentrated sulfuric acid containing sulfur trioxide.

2. Process according to claim 1, which comprises using as the strongacid reagent concentrated sulfuric acid containing from about 0.1percent to about 20 percent of sulfur trioxide.

3. Process according to claim 1, which comprises using as the strongacid reagent concentrated sulfuric acid containing from about 0.5percent to about 5 percent of sulfur trioxide.

4. Process according to claim 1, which comprises using2,3-bis-(3-pyridyl)-butan-2,3-diol as the starting material.

5. Process for the preparation of 2-methyl-1,2-bis-(3-pyridyl)-propan-1-one, which comprises treating 2,3-bis-(3-pyridyl)-butan-2,3-diol with concentrated sulfuric acid containingsulfur trioxide.

Ingold: Structure and Mechanism in Org. Chem. (Cornell), pages 202-4,300 (1953).

Royals: Advanced Org. Chem. (Prentice-Hall), 252- 3 (1954).

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No 3 ll8898 January 21 1964 William Lassiter Yost It is hereby certified thaterror appears in the above numbered patent requiring correction and thatthe said Letters Patent should read as corrected below.

Column 3 line 37 for Serial N0, 96 11l' read me Serial N0, 96 112 Signedand sealed this 9th day of- June 1964,

(SEAL) Attest:

EDWARD J. BRENNER Commissioner of Patents ERNEST W. SWIDER AttestingOfficer

1. IN THE PROCESS FOR THE PREPARATION OF 2,2-DI-LOWERALKYL-1,2-BIS-PYRIDYL-ETHAN-1-ONES BY TREATMENT WITH A STRONG ACIDREAGENT OF A MEMBER SELECTED FROM THE GROUP CONSISTING OF A 1,2-DI-LOWERALKYL-1,2-BIS-PYRIDYL-ETHAN-1,2DIOL AND A SALT THEREOF, THE IMPROVEMENTWHICH COMPIRSES USING AS THE STRONG ACID REAGENT CONCENTRATED SULFURICACID CONTAINING SULFUR TRIOXIDE.